It seems a very long time ago that I wrote a series of posts on the mechanism of the development of the arterial tunica intima from a single layer of cells through to a thickened structure of similar or greater thickness than the muscularis layer. I've gone back and re-labelled them under Arteriosclerosis (1) through to (5).
Very briefly:
Arteriosclerosis (1) covered the development of diffuse intima thickening (DIT) from birth through to about three years of age. DIT occurs over areas of disrupted elastin, is on the lumenal side of the elastin and is largely composted of glycosaminoglycans (GAG) and a few cells.
Arteriosclerosis (2) covered the role of platelets in supplying ILGF-1 which generates GAG at the site of platelet adhesion. That is where the platelets stick to damaged endothelium and strengthen an area at which the elastic tissue has been ruptured. It is a physiological process of tissue reinforcement.
Arteriosclerosis (3) covered the condition of von Willebrand's Disease, where platelets fail to adhere to damaged tissue. In this condition the intima stays thin and there is no DIT with age, assuming the vWD is not fatal at a young age. The elastin layer gets completely trashed as there no ability to generate reinforcement.
Arteriosclerosis (4) illustrated this process by showing the formation of surface microthombi to deliver platelets and generate GAG, it covered mucoplysaccaride disorders with massive intimal thickening when GAG cannot be degraded/remodelled and introduced the idea of intimal thickening in the arterial supply to the atrioventricular node as a precursor to sudden cardiac death.
Arteriosclerosis (5) is just the pictures to complete part (4).
To summarise: Arteriosclerosis begins as non pathological DIT which is a reinforcement system to maximise the correct development of the arterial tree to best withstand the loads to which it is subjected. It gives a tailor-made cardiovascular system for a given individual.
That's normal.
Subbotin has recently published
a review article documenting his view that pathological arteriosclerosis, with lipid infiltration, commences when the tunica intima becomes too thickened to receive adequate oxygenation without developing a vascular supply of its own. It is normally avascular, getting oxygen and nutrients by diffusion from either the arterial lumen or the arterioles embedded in the muscularis layer. Once the thickened tunica intima develops a vascular supply all hell breaks loose with apoB labelled lipids attaching themselves to the GAG on the mistaken basis that this the extra cellular matrix of damaged tissue.
This is a highly plausible scenario and fits with the microscopy much better than any fairytale about apoB lipoproteins sneaking through the arterial endothelium and burrowing deep, deep in to the intima before depositing themselves on the border with the muscularis layer, leaving the surface layer completely unaffected. Which is what the histology shows. Shrug. Never forget: Only purple spotted cholesterol causes CVD, anything else is bollocks.
There are several things which spring to mind about DIT, insulin and oxygenation. If, as I think likely, a general thickening occurs under the effect of chronic hyperinsulinaemia acting on the ILGF-1 receptors which are on the lookout for platelets, we have a reason why insulin, not glucose, drives CVD. Anything which hastens thickening of the tunica intima hastens CVD. Insulin.
Second is that not only do VLC diets drop insulin, but they also
reduce tissue oxygen extraction while maintaining normal ATP production. If Subbotin is correct that localised tissue hypoxia is what converts a benign reinforcement area to a fragile pool of lipid, then acetoacetate and beta-hydroxybutyrate (and stearic acid) are your first obvious port of call. AcAc/BHB looks like an excellent tool to blunt the impact of hypoxia on the need for blood vessel invasion of a given tissue.
Third: What happens if you keep insulin high with a diet of complete crap while supplementing ketone esters to reduce tissue oxygen needs? My guess, and it's only a guess, is that intimal thickening will progress apace but will only develop vascularisation at a later stage of the process, when the slack provided by the exogenous ketones has been taken up. Equally, the worry might be that you take ketone esters for a year, living on crap, and then run out of funds while you have thickened avascular DIT which was quite happy under ketones but is then going to need more oxygen per unit ATP under glucose oxidation. At least by going the ketogenic diet route you should have had basal insulin to minimise DIT progression in combination with your AcAc/BHB, up until the time you feel that you'd rather die than continue to live without eating pizza.......
Peter
